The long-term goal of this project is to characterize effect of dietary methylxanthines (MX) on plasma fluoride (F). We have shown for the first time that concomitant ingestion of sodium fluoride (NaF) and MX or MX-containing beverages by rats resulted in plasma level significantly higher than that by ingestion of NaF with water. Studies are proposed to determine if stimulation of gastric secretion by MX will favor the formation of HF and facilitate the absorption of F from the stomach. Degree of F absorption from the stomach under the influence of MX will be compared to that from proximal small intestine. Known inhibitors of gastric secretion will be used to verify the role of gastric secretion in F uptake. NaF, MFP, APF and SnF2 are frequently used by clinicians, although they differ in pH, dissociation constants, and mode of gastrointestinal absorption. We propose to study if absorption of these compounds varied under the influence of dietary MX. Effects of dietary MX on bioavailability, excretion, and retention of F will also be studied. Effects of age, sex and species on MX- induced plasma F increase will be determined. In addition, effects of dietary MX on enamel fluorosis will be studied in rats. Information obtained could explain the occurrence of fluorosis in communities where the level of F uptake should not cause this disorder. Ingested caffeine is readily absorbed and present in breast milk. Hence, studies are assigned to show if pups nursed by dams on MX-containing diet will have a higher plasma and greater risk to fluorosis. Pending outcome of these studies, the recommended supplement dosage may be adjusted to reflect the caffeine consumption habits of children; pregnant mothers may have to avoid MX-containing diet; residents in communities with excessive water F levels may need to be advised of the added risk of fluorosis n using MX-containing diet. Furthermore, children being treated with theophylline r other MX may need to adjust the F intake. Contrariwise, caffeinated beverages may be used to deliver F in communities with low water F. Similarly, this will enable the use of a smaller dose of F in treatment of patients with osteoporosis and alleviate he unpleasant side effects caused by present dosage. In toto, the proposed research could provide basic information for a better understanding of biopharmacokinetic actions f MX and the mechanism(s) involved in the effect of dietary MX on plasma F level. Above all, information obtained here could lead to a direct clinical application in prevention of dental caries, dental fluorosis and treatment of osteoporosis